Recent studies have revealed that the pathogenesis of various diseases is basically due to abnormal functions of the apoptosis signal transduction system. Apoptosis modulating therapy is designed to control cell growth and death by inducing or suppressing apoptosis, with the aim of fundamentally healing diseases by converting abnormal cells to a normal state as well as halting the progression of diseases by the apoptosis of abnormal cells. Hence, a cell survival-death reversible controlling technology is determined to be the next generation of core technology for apoptosis modulating therapy.
Apoptosis modulating therapy, which is now competitively being developed around the world, can find applications in the treatment of various diseases including leukemia, cancer, Alzheimer's disease, Parkinson's disease, AIDS, senescence and degenerative diseases, and heart diseases. However, apoptosis modulating therapy is arising as a fundamental technique applicable to a wider spectrum of diseases as abnormal functions of the apoptosis signal transduction system are revealed to account for the onset of most diseases.
Configured to either suppress the pathological growth of uncontrollable cells such as cancerous cells or prevent normal cells from undergoing excessive apoptosis as in heart diseases, apoptosis modulating therapy can be used in the therapy of diseases. For cancer, for example, conventional chemotherapy, characterized by causing necrosis over a wide range of cells, not only kills pathological cells, but also exhibits cytotoxicity to normal cells with the concomitant induction of excessive inflammation, as cytotoxic enzymes (e.g., lysozymes) are released upon the lysis of the pathological cells. In contrast, apoptosis modulating therapy induces pathological cells to undergo apoptosis or strongly suppresses the growth of pathological cells without the inflammatory side effects caused by the necrosis of cancer cells. When cells are under the potent power of growth inhibition, cancer cells are more greatly restrained from growing than are normal cells because of the greater proliferative activity of cancer cells. If this inhibitory effect is maximized to induce apoptosis, various cytotoxic intracellular materials are for the most part digested by caspase during apoptosis to lose their functions while being surrounded by apoptotic bodies and subsequently phagocytosed by macrophages. During the phagocytosis, the cytotoxic factors are neither released extracellularly nor exert cytotoxicity on surrounding cells.
Programmed cell death (apoptosis) is active death of cells requiring energy, with the accompaniment of characteristic morphological changes. Given an apoptotic signal, a cell determines to destroy itself and commits suicide. In this phase, the cell undergoes biochemical events which lead to morphological changes. Once apoptosis proceeds, cells shrink and separate from adjacent cells, showing membrane blebbing, chromatic condensation, and chromosomal DNA fragmentation and forming apoptotic bodies that macrophages are able to engulf and quickly remove before the contents of the cell can spill out onto surrounding cells and cause damage. Apoptosis is a complex intracellular process. Although not easily determined, apoptosis may be achieved via various downstream pathways once it is triggered. Caspases, which are aspartic acid specific cysteine proteases, are responsible for most morphological changes which take place during apoptosis.
Within the scope of diseases associated with cell death is ischemic heart disease. Ischemic heart disease is characterized by ischemia to the heart muscle, that is, a significant shortage of oxygen needed for cellular metabolism to keep tissue alive, due to the restriction of blood supply to the heart, resulting in the death of cardiomyoctes and the functional impediment of myocardia. That is, ischemic heart disease may ultimately lead to irreversible injury of the myocardium, i.e., necrosis of cells and tissues. In the early stage of ischemia in which the injury is reversible, it can be prevented from progressing to a fatal degree by reperfusion therapy including surgery, such as percutaneous transluminal coronary angioplasty and coronary artery bypass grafting, and drug therapy, such as thrombolytic therapy. However, even after such reperfusion therapy, there is high incidence of reperfusion injuries such as recurrence of myocardial infarction, cardiac dysfunction, arrhythmia, cognitive impairment, etc. Given ischemia/reperfusion injury, heart diseases, such as myocardial infarction, arrhythmia, cardiac dysfunction, etc., occur with a high prevalence rate and mortality and are difficult to heal. Examples of ischemic heart diseases include coronary artery disease, stable angina, unstable angina, variant angina, myocardial infarction, sudden death, sudden cardiac death, cardiac arrest, heart attack, and the like.
Albumin is a multifunctional protein which is most abundantly found in blood plasma. This plasma protein is produced mainly in the liver and is a major component of most extracellular fluids including interstitial fluid, lymph, and cerebrospinal fluid. Since a reduced level of albumins may lead to hepatic dysfunction and malnutrition, albumin has been extensively used for critical conditions including vascular collapse in serious patients or hepatic cirrhosis patients in clinics. In addition, recent research has suggested that albumin specifically binds to low-molecular weight molecules that might be important diagnostic or prognostic indicators of diseases. For example, albumin is reported to enter the brain across the blood-brain barrier by molecular diffusion and also to be implicated in Alzheimer's disease because it can specifically bind to and transport amyloid beta 1-42 (Aβ1-42). It is also known that albumin can be synthesized in microglial cells, a kind of cell of the mononuclear phagocyte system, in the brain and that the synthesis and extracellular secretion of albumin from microglial cells increases upon microglial activation with Aβ1-42.
Advanced glycation end-products (AGEs) are complex products which are incessantly produced inside the body mainly by reactions between carbohydrates and free amino acids. AGEs are chemically very unstable and reactive and are known as potent molecules that promote neuronal cell death. AGEs are also reported to be found in increased levels in the brain of senile persons or animals, and to exert influence on all cells and biological molecules, causing senescence and senescence-related chronic diseases. That is, AGEs are involved in senescence, Alzheimer's disease, renal disease, diabetes mellitus, diabetic vascular complications, diabetic retinopathy, and diabetic neuropathy, by enhancing vascular permeability, suppressing vasodilation via nitrogen oxide interference, and increasing LDL oxidation, the release of various cytokines from macrophages or endothelial cells, and oxidative stress.
Since AGEs are found, as described above, at an elevated level in the brains of senile persons or animals, and exert influence on most cells, causing senescence and senescence-related chronic diseases, many scientists have suggested that AGEs might have influence on neurodegenerative diseases such as Alzheimer's disease by promoting neuronal cell death. In spite of extensive research results, the precise synthesis mechanism or main secretion places of AGEs still remain unknown. Hence, the discovery of the precise synthesis mechanism and origin of AGEs may be helpful in finding a method for inhibiting the induction of cell death, thus contributing a clue to the etiology of various diseases. There is therefore a need for researching the precise synthesis mechanism of AGEs by which the pathology of various diseases, inter alia, ischemic heart diseases, can be revealed.